Nitric oxide acts as a "brake" on myocardial function and metabolism. It acts through the production of the second messenger cyclic GMP. During heart failure, cyclic GMP's "braking" effects are reduced although its level increases. There are conflicting reports on the changes in the myocardial functional effects of nitric oxide in aging, although the some of its vascular effects diminish with age. Therefore, we hypothesize: 1. The myocardial functional effects of nitric oxide will be reduced with aging. 2. These changes will, in part, be related to changes in the heart's ability to produce and degrade cyclic GMP. These hypotheses will be studied in isolated young and old rabbit cardiac myocytes as well as in young and aged hearts of anesthetized open-chest rabbits. Myocyte O2 consumption will be measured using oxygen electrodes. Myocyte functional parameters, percent shortening, etc., will be determined using a video edge detector. Nitric oxide synthase will be examined by immunocytochemistry and cyclic GMP levels will be determined by radioimmunoassay. Agents will be added to the young and old ventricular myocytes to alter the level of nitric oxide and/or cyclic GMP. Additional studies will be conducted in vivo on the hearts of anesthetized open-chest rabbits. We will determine regional wall thickening, regional O2 consumption, coronary blood flow and local O2 extraction, endothelial nitric oxide synthase, cyclic GMP, guanylate cyclase and cyclic GMP-phosphodiesterase activity. Agents will be applied to the myocardial surface to alter the myocardial nitric oxide or cyclic GMP levels. The in vivo studies will allow us to determine the importance of the in vitro effects. With the development of our ability to measure myocyte and regional second messenger levels, function and O2 consumption, this grant allows, for the first time, determination of the basic mechanisms through which nitric oxide and cyclic GMP controls function and O2 cost and how aging affects these parameters. If loss of the braking function of nitric oxide on the heart is part of the aging process, we may be able to develop new treatments for cardiovascular problems associated with the aging process.